Exercise training enhances multiple mechanisms of relaxation in coronary arteries from ischemic hearts

Abstract

Deer RR, Heaps CL. Exercise training enhances multiple mechanisms of relaxation in coronary arteries from ischemic hearts. Am J Physiol Heart Circ Physiol 305: H1321-H1331, 2013. First published August 30, 2013; doi:10.1152/ajpheart.00531.2013.-Exercise training of coronary artery disease patients is of considerable interest, since it has been shown to improve vascular function and, thereby, enhance blood flow into compromised myocardial regions. However, the mechanisms underlying exercise-induced improvements in vascular function have not been fully elucidated. We tested the hypothesis that exercise training increases the contribution of multiple mediators to endothelium-dependent relaxation of coronary arteries in the underlying setting of chronic coronary artery occlusion. To induce gradual occlusion, an ameroid constrictor was placed around the proximal left circumflex coronary artery in Yucatan miniature swine. At 8 wk postoperatively, pigs were randomly assigned to sedentary or exercise (treadmill, 5 days/wk) regimens for 14 wk. Exercise training significantly enhanced the contribution of nitric oxide, prostanoids, and large-conductance Ca 2ϩ -dependent K ϩ (BKCa) channels to endothelium-dependent, bradykinin-mediated relaxation in nonoccluded and collateral-dependent arteries. Combined nitric oxide synthase, prostanoid, and BK Ca channel inhibition ablated the enhanced relaxation associated with exercise training. Exercise training significantly increased nitric oxide levels in response to bradykinin in endothelial cells isolated from nonoccluded and collateral-dependent arteries. Bradykinin treatment significantly increased PGI 2 levels in all artery treatment groups and tended to be further enhanced after nitric oxide synthase inhibition in exercise-trained pigs. No differences were found in whole cell BK Ca channel currents, BKCa channel protein levels, or arterial cyclic nucleotide levels. Although redundant, upregulation of parallel vasodilator pathways appears to contribute to enhanced endothelium-dependent relaxation, potentially providing a more refined control of blood flow after exercise training. exercise; endothelium; chronic coronary artery occlusion THE ENDOTHELIUM PLAYS AN IMPORTANT role in mediating vascular tone. In response to mechanical stimuli (shear stress and pulsatile pressure) or vasoactive agonists (bradykinin and acetylcholine), endothelium-dependent relaxation occurs through the release of mediators such as nitric oxide and PGI 2 , which affect the adjacent vascular smooth muscle in a paracrine manner. In addition, a third endothelium-derived factor [endothelium-derived hyperpolarizing factor (EDHF)] relaxes vascular smooth muscle by causing hyperpolarization of the underlying smooth muscle cells. While a single EDHF has not been elucidated, numerous candidate mechanisms or pathways have been proposed. Large-conductance Ca 2ϩ -dependent K ϩ (BK Ca ) channels are a common downstream effector for several of these potential EDHFs (2, 27), as well as for nitric oxide (29) and PGI 2 ...

Exercise Training‐Induced Adaptations in Mediators of Sustained Endothelium‐Dependent Coronary Artery Relaxation in a Porcine Model of Ischemic Heart Disease

“…Furthermore, our previous studies in coronary arteries from chronically occluded pigs have revealed that treatment with the prostanoid inhibitor, INDO, did not significantly alter bradykininmediated relaxation responses compared with control (no inhibitor) conditions in any of the artery treatment groups (i.e. nonoccluded or collateral-dependent of SED or EX pigs) [5]. We also reported recently that prostanoid inhibition had no effect on bradykinin-mediated relaxation until combined with NOS inhibition [5].…”

“…nonoccluded or collateral‐dependent of SED or EX pigs) . We also reported recently that prostanoid inhibition had no effect on bradykinin‐mediated relaxation until combined with NOS inhibition . These data suggested compensation for nitric oxide inhibition by prostanoids and thus, we included INDO in all experiments to control for this compensatory mechanism in arterial relaxation.…”

Cardiovascular Adaptations to Exercise Training

“…Studies have shown that a period of exercise training increases the protein concentration of prostacyclin synthase and COX-1 in skeletal muscle tissue (135,175) although this has not been observed in all studies (161). In animal studies, training-induced improvements in endothelial dependent vasodilatation via bradykinine and acetylcholine are partly dependent on prostaglandins (86,87). Moreover, in individuals with essential hypertension, training enhances the increase in muscle interstitial prostacyclin in response to adenosine infusion (175) and improves the balance between basal prostacyclin and thromboxane levels in the muscle interstitium (161).…”

Regulation of Coronary Blood Flow

“…Similarly, impairments in SK Ca and IK Ca channels contribute to the endothelial dysfunction of coronary arterioles from diabetic patients (623). In comparison, endurance exercise training enhances the contribution of BK Ca channels to endothelium-dependent relaxation of arteries taken from ischemic areas of the swine heart (234). …”